donor stem cell transplant, pentostatin, and total-body irradiation in treating patients with hematological cancer

Conditions: Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Myelodysplastic Syndromes; Nonmalignant Neoplasm

Summary: rationale: giving low doses of chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. it may also stop the patient's immune system from rejecting the donor's stem cells. the donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. removing the t cells from the donor cells before transplant and giving cyclosporine and mycophenolate mofetil after transplant may stop this from happening. purpose: this phase i/ii trial is studying the side effects of giving a donor stem cell transplant after pentostatin and total-body irradiation and to see how well it works in treating patients with hematological cancer.

objectives: primary * to determine the safety of pentostatin and low-dose total body irradiation followed by t-cell-reduced unrelated donor peripheral blood stem cell transplantation, in terms of regimen-related toxicity, in patients with hematological malignancies. * to evaluate the efficacy of this regimen, measured as engraftment rate and establishment of donor hematopoietic chimerism, in these patients. secondary * to determine the incidence of acute and chronic graft-versus-host disease in patients treated with this regimen. outline: * reduced-intensity preparative regimen: patients receive pentostatin iv over 30 minutes once daily on days -10 to -8 and undergo low-dose total-body irradiation on day -1. * unrelated donor peripheral blood stem cell transplantation (pbsct): patients undergo t-cell-reduced donor pbsct on day 0. * graft-versus-host disease (gvhd) prophylaxis: patients receive cyclosporine iv over 2 hours twice daily on days -1, 0, and 1 and then orally twice daily on days 2-70 followed by a taper in the absence of gvhd. patients also receive oral mycophenolate mofetil twice daily on days 0-27 followed by a taper. patients undergo bone marrow aspirate and biopsies and blood sample collection periodically for laboratory studies. samples are analyzed for cytokines (i.e., il-6, tnf-γ, il-1β, and il-10) by elisa; phenotypic, molecular, and functional analysis of immunologic reconstitution markers (i.e., pha, il-2, il-4, il-10, il-12, fas, fasl, tnf, tgf-β, and ifn-γ) by flow cytometry; and cytogenetics by fish. after completion of study treatment, patients are followed periodically.

Eligibility criteria:
inclusion criteria • diagnosis of a confirmed hematological malignancy that has relapsed or is at high risk for relapsing, including any of the following: acute myeloid leukemia (aml) meeting any of the following criteria: antecedent hematologic disorder therapy related primary induction failure in first complete remission (cr1) with poor-risk cytogenetics, as defined by the following: del(5q)/-5 del(7q)/-7 abn(3q) t(6;9) del(20q) del(17p) +13 complex karyotype t(9;22) = 11q23 rearrangement in second complete remission (cr2) or greater acute lymphoblastic leukemia meeting any of the following criteria: in cr1 with wbc \> 50,000/mm³ at diagnosis in cr1 with poor-risk cytogenetics (i.e., t\[9;22\], t\[1;19\], t\[4;11\]) and meets at least 1 of the following criteria: 19-75 years of age and received prior high-dose chemotherapy, total-body irradiation (tbi), or a radiation dose that precludes administration of 12 gy of tbi = 50-75 years of age = 19-75 years of age with hematopoietic stem cell transplantation (hsct) comorbidity index ≥ 3 cns or testicular involvement at diagnosis no cr within 4 weeks of initial treatment primary induction failure in cr2 or greater myelodysplastic syndromes meeting the following criteria: intermediate-2 or high-risk category as determined by international prognostic scoring system not considered a candidate for intensive or standard chemotherapy or hsct chronic myelogenous leukemia meeting any of the following criteria: first chronic phase and \ 5% and/or other evidence of progression to acute leukemia chronic myelomonocytic leukemia severe aplastic anemia failed prior antithymocyte globulin and cyclosporine immunosuppressive therapy mantle cell lymphoma meeting any of the following criteria: in cr1 in first partial remission (pr1) in cr2 or greater in second pr (pr2) or greater indolent non-hodgkin lymphoma or chronic lymphocytic leukemia meeting either of the following criteria: in cr2 or greater in pr2 or greater lymphoblastic lymphoma in cr1 or greater must have minimal residual disease as defined by either of the following: no more than 5% blasts in blood and/or bone marrow (in patients with acute leukemia/mds) no bulky adenopathy (\> 5 cm masses) and/or \< 20% bone marrow involvement by lymphoma (in patients with lymphoma) no progressive disease within 8 weeks of most recent prior therapy or within 12 weeks of prior autologous hsct no active cns malignancy (i.e., known positive csf cytology or parenchymal lesions visible by ct scan or mri) hla-matched unrelated peripheral blood stem cell donor available meets the university of nebraska medical center's or the national marrow donor program's criteria for donors matched at 7/8 or 8/8 hla-a, b, c, or drβ1 loci by molecular typing if match is not at allele level, suitability for donation requires discussion with and approval by the principal investigator not an identical twin karnofsky performance status 60-100% creatinine clearance ≥ 55 ml/min total bilirubin ≤ 2 times upper limit of normal (uln) (unless due to gilbert's disease or malignancy) alt and ast ≤ 4 times uln dlco ≥ 40% fev1/fvc ratio ≥ 50% of predicted cardiac ejection fraction ≥ 40%prior cytoreductive chemotherapy or irradiation to areas of bulky disease allowed, as determined by the primary physician in consultation with the study investigators exclusion criteria no cr within 4 weeks of initial treatment no other concurrent anti-tumor therapy not pregnant or nursing (fertile patients must use effective contraception) not receiving supplementary continuous oxygen no nyha grade ii-iv cardiac disease hiv positive active hepatitis b (i.e., positive hbsag and/or positive hbeag or high copy number on quantitative rna testing) or hepatitis c active uncontrolled infection or immediate life-threatening condition uncontrolled medical illnesses (e.g., uncontrolled systemic hypertension or diabetes)

Keywords: adult acute myeloid leukemia with 11q23 (mll) abnormalities adult acute myeloid leukemia with inv(16)(p13;q22) adult acute myeloid leukemia with t(15;17)(q22;q12) adult acute myeloid leukemia with t(16;16)(p13;q22) adult acute myeloid leukemia with t(8;21)(q22;q22) adult acute myeloid leukemia in remission recurrent adult acute myeloid leukemia secondary acute myeloid leukemia adult acute lymphoblastic leukemia in remission recurrent adult acute lymphoblastic leukemia accelerated phase chronic myelogenous leukemia blastic phase chronic myelogenous leukemia chronic phase chronic myelogenous leukemia relapsing chronic myelogenous leukemia chronic myelomonocytic leukemia de novo myelodysplastic syndromes previously treated myelodysplastic syndromes secondary myelodysplastic syndromes essential thrombocythemia polycythemia vera primary myelofibrosis stage iii mantle cell lymphoma stage iv mantle cell lymphoma marginal zone b-cell lymphoma of mucosal lymphoid tissue nodal marginal zone b-cell lymphoma splenic marginal zone lymphoma stage iii adult lymphoblastic lymphoma stage iv adult lymphoblastic lymphoma aplastic anemia chronic eosinophilic leukemia chronic neutrophilic leukemia contiguous st ii adult diffuse small cleaved cell lymphoma noncontig stage ii adult diffuse small cleaved cell lymphoma stage i adult diffuse small cleaved cell lymphoma stage iii adult diffuse small cleaved cell lymphoma stage iv adult diffuse small cleaved cell lymphoma contiguous stage ii grade 1 follicular lymphoma contiguous stage ii grade 2 follicular lymphoma noncontiguous stage ii grade 1 follicular lymphoma noncontiguous stage ii grade 2 follicular lymphoma stage i grade 1 follicular lymphoma stage i grade 2 follicular lymphoma stage iii grade 1 follicular lymphoma stage iii grade 2 follicular lymphoma stage iv grade 1 follicular lymphoma stage iv grade 2 follicular lymphoma contiguous stage ii marginal zone lymphoma noncontiguous stage ii marginal zone lymphoma stage i marginal zone lymphoma stage iii marginal zone lymphoma stage iv marginal zone lymphoma contiguous stage ii small lymphocytic lymphoma noncontiguous stage ii small lymphocytic lymphoma stage i small lymphocytic lymphoma stage iii small lymphocytic lymphoma stage iv small lymphocytic lymphoma contiguous stage ii mantle cell lymphoma noncontiguous stage ii mantle cell lymphoma stage i mantle cell lymphoma contiguous stage ii adult lymphoblastic lymphoma noncontiguous stage ii adult lymphoblastic lymphoma stage i adult lymphoblastic lymphoma stage i chronic lymphocytic leukemia stage ii chronic lymphocytic leukemia stage iii chronic lymphocytic leukemia stage iv chronic lymphocytic leukemia